It has been established that tumor cells express receptors for growth factors and cytokines that stimulate proliferation of the cells and, moreover, that antibodies to such receptors (e.g., tyrosine kinase receptors) can be effective in blocking the stimulation of cell proliferation mediated by growth factors and cytokines to inhibit tumor cell growth. Commercially available therapeutic antibodies that target receptors on cancer cells include, for example, trastuzumab (Herceptin) for the treatment of breast cancer, which targets the HER2 receptor (also known as ErbB2), and cetuximab (Erbitux) for the treatment of colorectal cancer and head and neck cancer, which targets the epidermal growth factor receptor (EGFR, also known as HER1 or ErbB1).
While this approach of administering a therapeutic agent comprising only a single therapeutic monoclonal antibody (when administered in the absence of administration of another therapeutic antibody, referred to herein as monotherapy) has shown considerable success in cancer treatment, there are a number of factors that can lead to failure of such treatment or recurrence of tumor growth after initial inhibition. For example, certain tumors rely on more than one growth factor-mediated signal transduction pathway for cell proliferation and thus targeting of a single pathway may prove insufficient to significantly affect tumor cell growth. Alternatively, even in cases where one pathway is the only or predominant growth-stimulatory pathway, certain tumors cells are capable of activating another signaling pathway for growth stimulation when the original one is blocked by antibody (innate resistance to treatment). Still further, some tumors exhibit initial responsiveness to antibody monotherapy but later develop resistance to treatment by switching to use of another signaling pathway (acquired resistance to treatment). Furthermore, some receptors, such as a c-Met receptor, are stimulated by conventional antibodies (e.g., IgG antibodies) to transduce signals into a cell upon which they are expressed. Without intending to be bound by any particular theory of operation, this phenomenon is believed to result from the crosslink pairing of two receptors on the same cell by the paired, generally identical, antigen binding sites present on antibodies such as IgAs, IgDs, IgEs, IgGs and IgMs. Such stimulation may have the opposite effect to that which produces a therapeutic benefit—e.g., cell growth and replication may be upregulated by such anti-c-Met antibodies, rather than inhibited.
In embodiments, the interaction with a receptor or plurality of receptors (e.g., a c-Met receptor) and a composition of the invention results in an antagonist activity. In a particular embodiment, such interaction results in an antagonist activity and is substantially free or free of agonist activity. In an aspect, antagonist activity is useful for compositions and methods of inhibiting cancer.
Accordingly, additional therapeutic approaches for cancer treatment are needed to overcome limitations of antibody monotherapy and to provide other benefits.